The goals of this research project are to confirm and extend our preliminary observations that demethyl solfoxide (DMSO) inhibits intimal plaque formation in developing dietary cholesterol-induced atherosclerosis in rabbits and reduces the characteristic uptake and massive accumulation of cholesterol in tissues despite severe hypercholesterolemia. Both an in vivo and an in vitro experimental approach will be employed to study the effects of DMSO on several major events in the pathogenesis of atherosclerosis including smooth muscle cell proliferation, collagen formation and the cellular uptake and metabolism of cholesterol. To investigate the effects of DMSO on cell proliferation, cell kinetic studies will be performed in vivo utilizing radioautography and in vitro using cultured rabbit or human smooth muscle and endothelial cells. Collagen production and deposition will be localized in the intimal, medial and adventitial layers of arteries and in cultured cells chemically and by immunofluorescent antibody staining as to the relative amount of types 1 and 111 collagen formed. The activity of several post-ribosomal enzymes that modify the collagen alpha chains, including prolyl hydroxylase, glucosyl transferase, procollagen peptidases and lysyl oxidase will be measured to more clearly define the effects of DMSO on collagen hydroxylation, glycosylation, cleavage of precursor and cross-linking, respectively. To study the effects of DMSO on the in vivo metabolism of cholesterol, cholesterol turnover, fecal bile acids, the distribution of plasma lipoproteins and the cholesterol content of body tissues will be measured. Cholesterol uptake and metabolism will be studied in vitro using cultured vascular cells. Because atherosclerosis develops in humans with mild hypercholesterolemia, atherosclerosis in rabbits will be induced by mild mechanical injury in the absence of overt hypercholesterolemia to determine whether DMSO can effectively reduce the severity of the subsequently induced fibromuscular lesions. In addition, studies will be performed to determine whether DMSO can effect the regression of established atherosclerosis in rabbits previously induced by intermittent dietary-cholesterol or mechanical injury.